Bronchiolitis is the leading cause of admissions in children less than two years of age. It has been recognized as highly debated for many decades. Despite the abundance of literature and the well-recognized importance of palivizumab in the high risk groups, and despite the existence of numerous, high-quality, recent guidelines on bronchiolitis, the number of admissions continues to increase. Only supportive therapy and few therapeutic interventions are evidence based and proved to be effective. Since Respiratory Syncytial Virus (RSV) is the major cause of bronchiolitis, we will focus on this virus mostly in high risk groups like the premature babies and children with chronic lung disease and cardiac abnormalities. Further, the prevention of RSV with palivizumab in the high risk groups is effective and well known since 1998; we will discuss the updated criteria for allocating infants to this treatment, as this medication is expensive and should be utilized in the best condition. Usually, diagnosis of bronchiolitis is not challenging, however there has been historically no universally accepted and validated scoring system to assess the severity of the condition. Severe RSV, especially in high risk children, is unique because it can cause serious respiratory sequelae. Currently there is no effective curative treatment for bronchiolitis. The utility of different therapeutic interventions is worth a discussion.

This guideline was prepared by the Saudi Pediatric Pulmonology Association - a subsidiary of the Saudi thoracic society - when noted how common are such conditions in the country and how urgent it is to have a national guideline according to the latest and best evidence-based practice. This guideline aims to help pediatricians and general practitioners when managing such conditions.

Abstract

Bronchiolitis is the leading cause of admissions in children <2 years of age. It has been recognized as highly debated for many decades. Despite the abundance of literature and the well-recognized importance of palivizumab in the high-risk groups, and despite the existence of numerous, high-quality, recent guidelines on bronchiolitis, the number of admissions continues to increase. Only supportive therapy and few therapeutic interventions are evidence-based and proved to be effective. Since respiratory syncytial virus (RSV) is the major cause of bronchiolitis, we will focus on this virus mostly in high-risk groups like the premature babies and children with chronic lung disease (CLD) and cardiac abnormalities. Further, the prevention of RSV with palivizumab in the high-risk groups is effective and well known since 1998; we will discuss the updated criteria for allocating infants to this treatment, as this medication is expensive and should be utilized in the best condition. Usually, diagnosis of bronchiolitis is not challenging. However, there has been historically no universally accepted and validated the scoring system to assess the severity of the condition. Severe RSV, especially in high-risk children, is unique because it can cause serious respiratory sequelae. Currently, there is no effective curative treatment for bronchiolitis. The utility of different therapeutic interventions is worth a discussion.

Definition

Bronchiolitis is the most common acute lower respiratory tract viral infection in infants <2 years of age.[1],[2] This is a pathological description while bronchiolitis is a clinical description. Acutely, the inflammation is not limited to the bronchioles and is found in all parts of the airway further. In 2006, a subcommittee of the American Academy of Pediatrics (AAP) together with the European Respiratory Society (ERS) defined bronchiolitis as a constellation of clinical symptoms and signs including a viral respiratory prodrome followed by increased lower respiratory effort and wheezing in infants <2 years of age.[3] Children admitted for wheezing in the 2nd year of life are common; such could have different pathophysiology and different prognosis for this recent data limited bronchiolitis definition to the 1st year of life.[4] We reviewed numerous guidelines aiming to extract the best evidence in the management of bronchiolitis.[3],[5],[6],[7],[8]

Methods

We searched PubMed up to November 2015 using the following words in different combinations, bronchiolitis infant, guideline, pathophysiology, management, pharmacotherapy, acute, bronchodilator, steroid, oxygen, physiotherapy, hypertonic saline, intensive care, continuous positive airway pressure ventilation (CPAP), bi-level positive pressure ventilation, mechanical ventilation, antibiotic, and montelukast. The included studies where not systemically evaluated for the design and quality. Guidelines and Cochrane reviews were intensively reviewed.

To construct this guideline, the panel met twice. During the first meeting, the panel discussed the available evidence, while it graded the evidence during the second meeting. Grading the evidence was inspired from the recommendations in the center of evidence-based medicine website (www.cebm.net), listed by Burns et al.,[9] as below.

5 Expert opinion without explicit critical appraisal or based on physiology bench research or “ first principles.”

Epidemiology

Bronchiolitis is the most frequent disease in children <2 years and is the leading cause of hospital admissions in this age group; it is a seasonal disease, appearing most frequently as an epidemic during winter months.[10] Bronchiolitis is a well-recognized condition; it affects around 1%–3% of all healthy children and more than 10% in high-risk groups.[4] Bronchiolitis represents a large public health burden throughout the world where 2%–10% of cases require hospitalization.[11] About 5% of RSV bronchiolitis cases require Intensive Care Unit (ICU) admission.[12] Mortality is very low in developed countries, but reported high in the developing world possibly due to overcrowding, poor nutrition, high inoculation,[13],[14] and low medical care. Mortality is high in the high-risk groups reaching 47% in CLD and 49.7% in congenital heart disease (CHD) infants.[15] RSV is the predominant organism responsible for around 70% of bronchiolitis cases worldwide, the prevalence in the kingdom of Saudi Arabia has wide variation 25%–88%.[16],[17] RSV is a single-stranded RNA which belongs to the pneumoviridae family with two main subtypes, A and B.[18] RSV occurs in all parts of the world, especially during the winter time, and by the age of 2 years, the majority of children are already infected with RSV,[19],[20] but only 40% of them develop lower respiratory tract symptoms.[19] Children may present with a wide range of symptoms ranging from simple upper respiratory tract infection (URTI) to respiratory failure requiring ventilator support.[21] RSV usually has a mild course but occasionally become severe, especially in high-risk groups such as premature neonates, children with CHD, children with CLD and children <2 months of age.[18],[19],[22] The peak incidence of RSV bronchiolitis occurs in infants between one and 6 months of age.[23],[24] The season on the northern hemisphere often starts in late October and continues to April, usually peaking in January.[25] The natural immunity is of short duration, thus repeated infection is common which could explain the recurrence of bronchiolitis, particularly in high-risk groups.[26] There are multiple other viral pathogens implicated in bronchiolitis, and co-infection with two or more agents could occur in up to 30% of cases usually with Human metapneumovirus, rhinovirus, parainfluenzavirus, bocavirus, and AdenoVirus.[4],[27],[28],[29],[30]

Global Respiratory Syncytial Virus Burden

RSV is found throughout the world and is responsible for a large proportion of infant morbidity and mortality, and is the leading cause of acute respiratory infections in children.[52]

The global burden of RSV in 2015 is estimated to be 33.1 million (uncertainty range 21·6–50·3) episodes of RSV-acute lower respiratory tract infection (LRTI), which resulted in about 3.2 million (2.7–3.8) hospital admissions, and 59,600 (48,000–74,500) in-hospital deaths in children younger than 5 years. About 45% of hospital admissions and in-hospital deaths due to RSV-ALRI occur in children younger than 6 months.[53]

Respiratory Syncytial Virus Burden in Saudi

During a 6-year study in Saudi, 643 hospitalized cases of ALRI were investigated.[54] Among all samples, respiratory viruses were detected in 309 samples. The overall detection rate was 48.1%. Of the positive samples, RSV was identified most frequently with 295 cases, which accounted for 95.5% of the total viral agents. Approximately 245 cases were younger than 1 year. The highest rate of RSV infection was identified in infants during the first 6 months of life (P< 0.03). Of the 309 virus-positive samples, bronchiolitis was detected in 264 (85%), and pneumonia in 45 (14.5%). RSV was the most often causative agent of both diseases (bronchiolitis in 251 and pneumonia in 44) (P< 0.0001).[54]

Furthermore in another Saudi study,[55] of 200 tested (nasopharyngeal aspirates) samples, 70 were positive for RSV infection (35%) typing of the positive samples using duplex real-time polymerase chain reaction (PCR) indicated that 57.1% were type A viruses and 42.9% were type B. These results validate the implication of both virus subtypes in RSV infection of Saudi Arabia children during the winter season, with a slight dominance of type A viruses. In this study, the samples were grouped into four main age groups as follows: 0–6; 6–12 months; 1–2 and 2–3 years. The results showed that 70% of the RSV-positive samples were collected from children younger than 1 year and then, the incidence decreased as the age increased (18.6% during the 1nd year and 11.4% during the third year). Risk factors including male gender, young age (<1 year), and asthma may be the underlying factors that favor RSV infection in Saudi Arabia children.[55]

A third Saudi study [56] with a total of 10,617 patient specimens screened for respiratory viruses there was a total of 883 (8.3%) positive patients. Of these, 733 were positive for RSV, 62 positive for influenza, 79 positive for parainfluenza, and nine positive for adenovirus. Age distribution of patients showed that 92% of infections occurred in children aged 1 year and under. RSV is an important cause of LRTIs in infants often causing hospitalization. RSV infections occur primarily during annual outbreaks during winter months. In the mentioned study, RSV infections occurred between November and February with a peak during January. Those results are in agreement with other studies carried out in Saudi Arabia [57] in which RSV was the most frequent cause of bronchiolitis.[55]

A fourth Saudi study [58] which included 282 specimens, 128 (45.4%) were found to be positive for RSV. Most of the positive specimens came from patients <1-year-old (51.3%), RSV was strongly associated with patients who were <2 years old (47.2%, P = 0.019). The clinical observations from 128 children positive for RSV showed that RSV infection was significantly associated with bronchopneumonia (56.7%, P = 0.001) and bronchiolitis (55.4%, P = 0.002). Of the infected children, 47% and 36.7% were hospitalized for 1–4 and 5–8 days, respectively. The frequency of the signs and symptoms of the 128 children positive for RSV a cough and tachypnea were the most frequent, occurring in 100% and 98% of the children, respectively, followed by fever (81%), wheezing, crepitation, and retraction, each representing 66%. Three deaths were reported.[58]

Furthermore in a fifth study,[59] 19.3% of the nasopharyngeal aspirate samples for 4575 inpatients and outpatients with acute respiratory symptoms were positive for RSV. About 55% of the cases were male and 45% were female. Most of the cases were in the age group 0–6 months (58.9%), followed by the age group >6–12 months (19.8%). Seasonal variation showed that most of the RSV cases were predominant during winter and early spring months.[60]

Furthermore in another study,[33] prematurity, CLDs, atopic dermatitis, pure formula feeding, passive smoking, and age of 1 year were significant predictors of admission. RSV was the most common frequent cause of admitted cases of bronchiolitis. RSV was isolated in 40% of the admitted cases. About 80% of bronchiolitis due to RSV were in children <6 months of age.[33]

Risk factors associated with RSV infection in Saudi children admitted to the pediatric ICU (PICU) of a tertiary university hospital were investigated [61] prematurity was associated with increased severity of RSV infection. Nearly 37% of infants admitted in the PICU were found to be of premature birth. Moreover, children with pulmonary pathology and cardiovascular abnormalities were also more prone to RSV infection. From a span of 5 years follow up, the earliest RSV cases appeared in October and the latest cases were documented as late as April. Peak RSV admissions were from December to February. Prematurity, pulmonary pathology, neurological, and cardiovascular abnormalities are associated with increased severity of RSV infection.[61]

Virology

RSV is a highly contagious respiratory virus that infects the lungs and breathing passages.[31]

Nearly all children are infected with RSV by the age of 2 years.[31] RSV is the number one cause of acute respiratory tract infection (such as bronchitis and pneumonia) among children under 5 years of age and severe RSV infection is the primary cause of bronchiolitis in infants ≤2 years.[11],[31]

Healthy children infected with RSV generally experience disease of mild cold-like symptoms such as coughing, congestion, wheezing, sore throat, runny nose, and fever.[4],[5],[123] However, severe RSV disease can be fatal in infants and young children with the underlying conditions of prematurity, bronchopulmonary dysplasia (BPD), or CHD [5],[32],[33] Additional social and environmental risk factors associated with severe RSV infection include, but are not limited to, day care attendance, number of siblings, tobacco exposure, overcrowding, and a family history of asthma.[6]

Respiratory Syncytial Virus Nature

Human RSV, or RSV, is a member of the genus pneumovirus, of the family Paramyxoviridae. The virus is an enveloped, nonsegmented virus-containing a single negative-strand of ribonucleic acid (RNA).

The viral genome encodes ten proteins including two envelope proteins, F and G. The G protein mediates the attachment of the virus to the host cells and the F protein is involved in cell penetration and promotes cell-to-cell transmission through the formation of syncytia [47],[50],[51],[104] RSV can be classified into two strains, RSV-A and RSV-B, based their reactivity with antibodies directed against the variable G protein.[53]

RSV is the most common cause of bronchiolitis and pneumonia in children younger than 1 year of age in the US [105] It is estimated that severe RSV infection causes as much as 90% of all childhood bronchiolitis (inflammation of the bronchioles) and up to 40% of all childhood pneumonias.[5]

RSV infections are commonly limited to the respiratory tract and generally manifest as URTIs or LRTIs. RSV attaches to and enters the epithelial cells of the upper respiratory tract, where the virus replicates. RSV is then spread down the respiratory tract through cell-to-cell transfer along the syncytia (or intracytoplasmic bridges) from the upper respiratory tract to the lower respiratory tract.[58],[106]

The immunological response to RSV infection includes innate, cell-mediated, and humoral responses.[34] The innate immune system is the first-line of defense against infection and encompasses recruitment of phagocytic cells (neutrophils and macrophages) that initiate the release of a range of inflammatory cytokines.[35] Specifically, the F protein of RSV binds to Toll-like receptor 4 and CD14 on monocytes to stimulate the release additional cytokines. Among the components secreted by inflammatory cells, surfactant A is suggested to promote the clearance of RSV since surfactant A binds to and neutralizes RSV, while surfactant A-deficient in mice show impaired RSV clearance [36],[37] Experiments with the cell-mediated immune response in mice indicate that an inactivated vaccine to RSV induces a Th2 allergy associated response over the Th1 delayed hypersensitivity-related response.[38],[39]

In terms of nonimmunological factors, underdeveloped airways predispose infants to severe RSV disease. Lung development, i.e., its maturity, plays a major role in the development of RSV infections.[40]

Transmission of Respiratory Syncytial Virus

RSV is a highly transmissible virus and the only known reservoir for this virus is humans. However, RSV has been shown to survive on fomites (or objects or materials that are likely to carry infection), such as table tops for up to 6 h and on skin for up to 25 min [37],[41] Infants with RSV infection can shed virus for 1–2 weeks and in immunocompromised infants, this can increase up to several weeks.[42]

During periods of active viral shedding, RSV is predominantly transmitted by the following methods:

Contact transmission

RSV-contaminated respiratory secretions are commonly transmitted by direct contact and therefore, the rates of transmission may be greatly enhanced in crowded environments.[43]

Indirect transmission

RSV can be transmitted indirectly by contact with contaminated surfaces such as table tops or paper tissue. Furthermore, RSV can be transmitted indirectly by contaminated airborne droplets where particles are small enough to be inhaled into the respiratory tract. In 2009, aerosol samples were collected from an urgent care center in the United States and analyzed for viral RNA.[44] The study showed that RSV RNA was the most common virus detected in aerosol samples (32% in stationary samplers and 38% in personal samplers); these results support the hypothesis that RSV may be transmitted by airborne routes.[44]

Given that, RSV is highly transmissible through both direct and indirect contact with contaminated respiratory secretions, certain conditions can favor the rapid transmission of RSV, such as those in a pediatric hospital ward. A systematic review into nosocomial RSV infection showed that the risk of RSV transmission in neonatal or pediatric settings was between 6% and 56% (median: 28.5%) compared with 6% to 12% (median: 7%) in adult hospital units.[45]

Re-Infection of Respiratory Syncytial Virus

RSV infections are associated with high rates of re-infection. This high RSV re-infection rate is attributed to two strains of RSV (RSV-A and RSV-B) and the lack of long-term immunity. Infection with either strain can occur independently of the other, or both of them may occur simultaneously. The defining feature of the two RSV strains is in the variability of the G protein expressed on the surface of the virus. As such, neutralizing antibodies to one strain does not confer long-term immunity to the other [46] This lack of long-term immunity leaves infants susceptible to re-infection over time, as revealed by the Houston Family Study. During this study, it was observed that 98% of infants attending day care became infected with RSV during the 1st year of life, 74% were re-infected in year two and 65% in year three [47] A supportive study from Finland showed that the percentage of infants seropositive for RSV at 1, 2, and 3 years old was 37%, 68%, and 86%, respectively, indicating that younger infants are more likely to become re-infected due to low levels of antibody titers against RSV antigens.[48]

Although an infant's first RSV infection is usually the most severe and re-infection illnesses tend to be mild in healthy children, in some cases, re-infection can be severe, especially in high-risk infants.[49],[50] An expert consensus panel commented that even after a documented RSV infection in high-risk infants, a second RSV infection may occur within the same RSV season and can be severe enough to require hospitalization.[51]

Clinical Presentation

The majority of RSV bronchiolitis present with congested nose, runny nose and cough for the first 2 days, and 40% of cases will develop lower respiratory signs such as tachypnea wheezing, and crackles.[62] Hypoxia and cyanosis are common manifestations.[10] Symptoms usually peak as of day 4 until end of the 1st week,[63] then children show clear signs of improvement in the second week.[63] Incidence of apnea or acute life-threatening event in previously healthy infants is ≤1%, but reported as high as 23% in high-risk groups with prematurity.[18],[64] Clinicians should diagnose bronchiolitis and assess severity based on history and physical examination, and should assess the risk factors.[65] No single scoring system is used to assess the severity of bronchiolitis, nonetheless some suggestions for grading the severity of this disease is reported recently.[66] Recently, the Resvinet RSV expert network developed, validated and published a newly designed scoring system for severity of bronchiolitis named Resivnet scale. Its adoption in the clinical setting is likely to become frequent in the next years.[67]

Differential Diagnosis

In most cases, the diagnosis of bronchiolitis is clinically evident and further tests are not indicated,[10],[68] however, other diagnoses may be considered in an infant with atypical presentation. Many viruses other than RSV are implicated in the diagnosis of acute bronchiolitis, especially Human metapneumovirus, Parainfluenza and rhinovirus, Less commonly reported in literature are Influenza, Boca, and Adeno viruses.[69] Pertussis and mycoplasma could be concomitant infections.[70],[71] Aspiration is common in severe RSV bronchiolitis, attributed to the degree of respiratory distress.[72]

Bronchiolitis is difficult to distinguish from the first episode of asthma, especially in an atopic family or in a good responder to bronchodilator and steroids if used. Wheezes and crackles are common manifestations in multiple other respiratory conditions such as cystic fibrosis, ciliary dyskinesia, cardiac, or cases with immunodeficiency. In such conditions, detailed history and examination are enough to prioritize the differential diagnosis.

Investigation

Pulse oximetry

There is no clear international consensus regarding the lower accepted oxygen saturation in bronchiolitis.[73] Pulse oximetry should be included in the clinical assessment of bronchiolitis, it can detect hypoxemia not suspected by clinical assessment.[7] In general, there is a need for hospitalization when the oxygen saturation is ≤90% on room air,[4],[73],[74] while children with oxygen saturation more than 94% may be considered safe for discharge.[69] However, the decision-making for hospitalization of patients with oxygen saturation ranging between 91% and 94% on room air should be supported by detailed history and physical examination.[68],[69]

It is important to be aware that the adoption of different lower thresholds of saturation can highly impact on the hospitalization rates. Settings where hospitalization is mandatory for saturation levels of 92% or less will likely have lower hospitalization rates than settings where hospitalization is mandatory only – as an example for infants with saturation levels <94%. Therefore, it is mandatory to ensure at the very least-consistency, comparability and overall accuracy of the measurements, and (if possible) consistency between different settings of the criteria used to hospitalize.

With regard to the accuracy of measurements, the Panel recommends use of motion-tolerant instruments (level of evidence 1B). Furthermore, the Panel recommend accurate nasal suctioning (level of evidence 1B) before having the Saturation measurements taken.[75]

The panel recommends routine use of pulse oximetry for clinical assessment decision-making regarding hospitalization and discharge (level of evidence IB).

Management

Management of acute bronchiolitis is mainly supportive, where minimal handling approach seems to be beneficial in young age groups or in patients with significant respiratory distress.[4] All institutions caring for children with acute bronchiolitis should provide a clear treatment algorithm to their staff to minimize the burden of unnecessary procedure.

Oxygen therapy

Supplemental oxygen has not been studied adequately and it is difficult to choose a single point at which oxygen should be initiated.[78] The majority of investigators choose 92% rather 90% as reported recently by the APP. 2014.[78] Oxygen remains the mainstay of therapy in bronchiolitis, before initiating oxygen therapy, the accuracy of the initial reading should be verified by repositioning the probe and repeating the measurement [78],[79] Appropriate use of oxygen is an essential part in treating bronchiolitis, and is considered as a pharmacological agent.[78],[79] Oxygen can be delivered with different modalities according to the specific clinical needs. Oxygen needs always to be delivered heated and humidified. Use of nasal cannula, high-flow nasal cannula (HFNC), nasal CPAP can be considered. Initial rates of 0.5l/m for patients <6 m and at a rate of 1l/m for those more than 6 months are recommended [79] (level of evidence 1B). Severe cases may warrant intubation and mechanical ventilation. Some infants have abnormal baseline saturations, like in CLD, cardiac cases, and should be treated with caution.[80],[81]

Airway clearance

Nasal suctioning

The published guidelines recommend gentle and superficial suction before feeding or inhalation, aiming to clear the nostril, and improve the airway patency [82] (level of evidence 1B). There is no evidence to support the use of deep pharyngeal suctioning of the airway in bronchiolitis.[47],[82]

Chest physiotherapy and mist steam

Chest physiotherapy and mist steam does not improve the severity of the disease, respiratory parameters, nor reduce length of hospital stay or oxygen requirements in hospitalized infants with acute bronchiolitis not on mechanical ventilation.[83] There is insufficient evidence to show any benefit from steam inhalation.[83]

Feeding and hydration

Maintaining hydration is an important part in the management of acute bronchiolitis.[6] Children with mild respiratory distress can usually continue enteral feeds and only need observation. In patients with moderate respiratory distress and a respiratory rate that exceeds 60/min, feeding becomes compromised,[6] particularly in young age groups or in patients who have copious secretion, where the risk of incoordination and aspiration increases.[6],[84] Enteral feeding through oral gastric tube or nasogastric tube is recommended, and some kids benefit more from small frequent boluses or continuous feeding to minimize the risk of aspiration However, feeding increases basal metabolic rate, and puts patients at risk of dehydration.[6] In patients with severe respiratory distress, enteral feeding should be discontinued and parenteral fluids, such as sodium chloride and dextrose 5%, should be started [84] The AAP updates guidelines on bronchiolitis recommends nasogastric or intravenous fluid for moderate or severe cases who cannot maintain hydration orally.[6],[47]

Bronchodilators

Clinicians are still commonly using bronchodilators in bronchiolitis in 59%–100% of cases.[84],[85] However, there is a strong statement by the recent AAP Updates Guidelines on Bronchiolitis for not using salbutamol or adrenaline in bronchiolitis.[6],[86] Nonetheless, clinicians are often showing difficulty in complying with this recommendation.

The panel recommends the following (level of evidence 1B):

Bronchodilator should not be used routinely in bronchiolitis

On a case-by-case basis, a trial of bronchodilators may be performed, and the same drugs may not be discontinued only if there is a documented positive response from the treating team or if a scoring system is used, then more than one is needed to get a clear decision about continuing bronchodilators.

There is modest benefit from using racemic compared to salbutamol.[40],[87],[88],[89]

Hypertonic saline

There is growing evidence supporting the use of hypertonic saline in bronchiolitis. This idea started since 2002 by Sarell, Mendelberg [36],[90] as hypertonic saline improves mucociliary function in both diseased and healthy lungs.[38],[91] Hypertonic saline significantly reduces the length of hospitalization by 26% and improves illness severity;[37],[92] however, these points cannot be generalized at the level of the emergency department.[37] Hypertonic saline is generally administered in preparations containing a small amount of bronchodilator.

Due to the high safety profile,[41] low cost and noninvasive modality of administration, it looks reasonable to use hypertonic saline in the management of the bronchiolitis [37] as displayed by recent guidelines [6] (level of evidence 1B).

Glucocorticoid (inhaled and systemic)

Steroids are commonly used in the treatment of bronchiolitis, because of their anti-inflammatory effect. It is postulated that steroids decrease symptoms severity by minimizing airway edema and mucosal swelling. However, the Cochrane database, APP concludes that there is no clinical benefit of both systemic and inhaled steroids in reducing neither the rate of admission nor length of hospitalization.[44] In addition, inhaled steroids given in the acute phase are not beneficial in reducing the rate of postviral wheeze.[44] Their use is not routinely recommended in previously healthy infants with acute bronchiolitis.[45],[46],[48],[78],[93]

Combined inhaled steroid and bronchodilators

A large multicenter randomized trial which compared a combination of dexamethasone and nebulized epinephrine to placebo, and found that the investigation mixture may reduce the risk of admission on the 7th day of emergency visit; however, more evidence is still needed [94] (level of evidence 1B).

Antiviral

Ribavirin, a synthetic guanosine analog, is the only antiviral licensed medication that so far has been studied for the treatment of bronchiolitis.

Its use is highly controversial due to uncertainty about efficacy, safety, and high costs (CPS statement 2017). There are few reports that state that it could minimize the duration of illness in the ICU. The panel adopts the current Cochrane and APP recommendations, i.e., this drug should not be used routinely but might be considered only in specific patients affected by severe immunodeficiency syndromes, or severe CLD, or hemodynamically significant CHD [3],[49] (level of evidence 1A).

Antibiotics

Serious bacterial infection is rare in bronchiolitis where it accounts for an average of ≤2% of cases.[50],[51],[95] However, antibiotics are commonly prescribed in hospitalized patients, with rates comprised between 34%,[96] 45%[97] 2005, and even up to 95% in the ICUs as reported by Kneyber.[98]

Even for outpatients, antibiotics are excessively prescribed according to many reports from 53% to 99%.[96],[97],[98],[99],[100],[101]

Indications for antibiotics in bronchiolitis include cases complicated with otitis media or urinary tract infections.[3]

The use of antibiotics in very sick patients with CLD admitted in the ICU warrants further research, considering that bacterial colonization of the airways is frequently occurring in such patients.[97],[102]

The use of macrolides as anti-inflammatory agents is still debated and has no solid evidence so far.[103],[104],[105]

As a whole, there is no sufficient evidence to support the use of antibiotics in acute bronchiolitis. A recent Cochrane review recommends further research to determine the reasons for prescribing antibiotics, the correct indications, and how to reduce their use.[106],[107] The panel recommends that antibiotics should not be routinely used in the management of bronchiolitis unless there is a strong clinical suspicion of concomitant bacterial Infection or aspiration (level of evidence 1B). Antibiotic therapy may be considered in children with respiratory failure who require invasive ventilatory support.[102],[103]

Heliox

Heliox may improve the severity score in infants with acute RSV bronchiolitis, especially in the 1st h after commencing inhalation therapy. A systematic review of seven heterogeneous randomized trials of heliox for the treatment of moderate or severe bronchiolitis concluded that heliox did not reduce the rate of intubation, the rate of discharge from the emergency department, or the length of treatment for respiratory distress in PICU.[108] The panel states that heliox may be used as adjunctive therapy in critically ill children with RSV bronchiolitis (level of evidence 1A). However, further clinical studies are required to assess the efficacy of this therapy.

Noninvasive ventilation

CPAP can decrease the work of breathing and prevent endotracheal intubation in children with progressive hypoxemia or hypercarbia or in children who fail HFNC.[74]

Several studies showed that nasal CPAP is efficient in infants with bronchiolitis and severe respiratory distress, where it improves the breathing pattern and may be associated with decreased length of PICU stay.

The panel therefore highly recommends the use of CPAP to avoid endotracheal intubation in infants and children with bronchiolitis and severe respiratory distress or impending respiratory failure (level of evidence 2A).

Mechanical ventilation

Endotracheal intubation and mechanical ventilation are indicated in infants who have apnea or hypoxemia despite oxygen supplementation or in infants with worsening respiratory distress despite being on noninvasive ventilations such as CPAP or HFNC.

Endotracheal intubation and mechanical ventilation may also be required in cases with respiratory failure who failed other modalities and in high-risk groups, especially in patients younger than 3 months or those who had history of prematurity.[89] There is no consensus on which ventilator technique is the best for children with bronchiolitis [89] (level of evidence 2A).

Phenylephrine

There is no evidence that nasal phenylephrine 0.5% is effective in infants with acute bronchiolitis.[109]

The panel thus does not recommend the use of phenylephrine in the management of acute bronchiolitis (level of evidence 1B).

Anti-cholinergics

The role of anticholinergics in the management of bronchiolitis is uncertain.[110]

The panel thus does not recommend the use of anticholinergics in the management of acute bronchiolitis (level of evidence 1A).

Dornase Alfa (rhDNase Pulmozyme)

Although it might aid in the clearance of mucus and in relieving peripheral airway obstruction, a Cochrane review showed however that the administration of rhDNase does not reduce the length of hospital stay or the duration of supplemental oxygen in oxygen-dependent infants with RSV bronchiolitis.[111]

The panel thus does not recommend the use of rhDNase in the management of acute bronchiolitis (level of evidence 1B).

Surfactant

Abnormalities of surfactant quantity or quality have been observed in selected, severe cases of bronchiolitis.[112] Use of surfactant may be associated with a decrease in duration of mechanical ventilation and a decrease in ICU length of stay.[112] Some studies have also reported short-term benefit of surfactant on pulmonary mechanics and gas exchange [49] No adverse effects were found.[113] However, the studies are few and small, therefore the available evidence is still not sufficient to provide reliable evidence regarding positive effects of surfactant use in mechanically ventilated infants and children with severe bronchiolitis [112] (level of evidence 1A).

Anti-leukotriene (montelukast)

Bronchiolitis is an inflammation where the leukotriene pathway has been reported to be involved in the pathogenesis of the disease.[114] Accordingly, leukotriene inhibitors, such as montelukast, have been used in infants and young children with bronchiolitis [115],[116] The current evidence, however, does not show a clear benefit on the length of admission or on decreasing the chance of recurrent wheezing.[114],[115],[116] Based on this evidence, the panel does not recommend routine use of montelukast in the treatment of acute bronchiolitis (level of evidence 1B).

Identifying the causative virus

There are several methods to identify the virus

Rapid antigenic detection tests (RADTs): Widely used, inexpensive, quick, practical at the bedside, does not need laboratory-trained personnel and with a sensitivity of 80%–85%[76]

Direct fluorescent antibodies (DFA): This test is based on microscopic deletion of viral proteins on host cells via labeled antibodies, results take 2–4 h with sensitivity of 80%–97%[71],[72]

PCR: Expensive, not widely available, it is getting more popular, better than DFA [68],[72] and results take 2–24 h with sensitivity exceeding 90%[70],[77]

Viral culture: Rarely used, expensive and the results take 4 days to 2 weeks.[74]

The panel recommends using RADTs as first-line diagnostic tool (level of evidence 1B).

The sample for the RADT should be taken preferably through the nasal wash, rather than through nasal swab. Noteworthy, RADTs carry significant limitations due to their suboptimal sensitivity. Thus, confirmatory testing with PCR may be required for negative results in the presence of strong clinical suspicion and/or depending on surveillance reasons. PCR might be preferable also when nosocomial outbreaks need to 6 NRbe investigated/ruled out, and in episodes occurring in patients with primary or secondary immunodeficiency.

Radiological imaging

Chest X-rays are commonly requested for patients with bronchiolitis.[57],[74] The usual finding on X-ray includes hyperinflation and peribronchial wall infiltrates.[57],[74] In general, X-rays are not useful in bronchiolitis, and their use is associated with more prescription of antibiotics.[57],[74] However, the median recovery is the same at the end of the 1st week regardless of the X-ray findings.[57],[74] Hence, it is better not to use chest X-ray routinely in bronchiolitis, as recently published by AAP.[6]

The panel does not recommend routine use of chest X-ray as part of bronchiolitis management and recommends to reserve it for patients with complicated bronchiolitis such as secondary bacterial infection, aspiration or presence of other comorbidities (level of evidence 2B).

Laboratory investigation

Full blood count is commonly requested in bronchiolitis, but should not be performed in typical acute bronchiolitis.[6] Routine bacteriological testing (blood and urine) should be limited to the febrile patient or for atypical presentation.[8] Electrolytes, urea, and creatinine are usually normal and should not be measured.[3] Implementation of the guideline has shown the reduced use of diagnostic tests and therapeutic options with further reduction in the cost and length of stay.[4],[78]

Isolation

RSV inoculates mucous membranes and can survive up to 7 h on all hard surfaces, and can be transmitted directly or indirectly by touch.[86] It can be identified in the air as much as 22 feet from the patient bed.[68] Shedding of the virus can continue for 3 weeks in immunocompetent patients and for several months in immunocompromised ones.[86] Hygiene measures are therefore the cornerstone of any preventive strategy. Personal protective equipment, gloves, gown, and mask, should be used during the patient encounter. Of note, hand washing alone can decrease nosocomial RSV by 39%–50%.[117],[118],[119] Hospital inpatients with confirmed or suspected RSV should be placed in a private room under strict contact and droplet precautions. Contact and droplet precautions require the use of gowns, gloves, and surgical mask, and use of personalized stethoscopes. Accordingly, the panel recommends strict isolation of all patients presenting with suspected bronchiolitis. The panel stresses on the importance of strict hand washing practices and use of personal protective equipment (i.e., gloves and gowns) for preventing disease transmission. Among healt-hcare providers, the panel also recommends wearing masks during patient care encounters as exposure to aerosolized secretions is likely expected.

Prevention

Since effective anti-viral treatment for RSV is still lacking, RSV prevention remains of key importance. Comprehensive hygiene etiquettes are efficacious and cost-effective in preventing RSV spread, and should always be advocated as prophylactic measures.[1] In addition, secondhand smoking heightens risk for severe RSV infection requiring hospitalization, especially in late-preterm infants.[2] Accordingly, measures to reduce and prevent second-hand smoking are another cornerstone in RSV prevention. On a different note, breastfeeding, even in association with formula milk, reduces the risk of hospitalization for bronchiolitis during the 1st year of life (Lanari, 2013 #235). Thus, it is essential to encourage breastfeeding.

PaIivizumab

Palivizumab is a humanized monoclonal antibody produced by recombinant DNA technology that is a composite of human (95%) and murine (5%) antibody sequences.[120] It binds to the F protein of RSV F protein, which plays a role in virus attachment and mediates fusion, effectively neutralizing the virus and preventing its entry into the cell. Palivizumab was licensed in June 1998 by the US Food and Drug Administration for the reduction of severe LRTIs caused by the RSV in certain risk groups.

The efficacy and safety of palivizumab have been revealed in many prospective, retrospective, cohort and registry studies (Manzoni, 2017 #228). Among all the clinical studies, the most reliable evidence comes from three Phase III RCTs: The IMpact-RSV trial (1998),[100] the Feltes et al. study on critical congenital heart disease [15] the Blaanken et al. study (NEJM 2014).[128] These studies highlighted that Palivizumab is an effective form of prophylaxis that significantly reduces RSV-related hospitalization rates by 38%–80%, positively affecting a number of outcomes such as length of hospital stays, progression to ICU admission, duration of oxygen support, occurrence of wheezing episodes during the 1st year of age, mortality in high-risk populations.[15],[71],[72],[121]

In the first multi-center randomized double-blinded placebo-controlled trial (IMpact-RSV study), palivizumab showed 55% reduction (10.6% placebo vs. 4.8% palivizumab) in hospitalization as a result of RSV infection in premature babies.[15] In children with CHD, palivizumab was associated with a 45% reduction in RSV hospitalizations. Since then, AAP had updated the guidelines four times for better usage of this medication.[3],[122],[123],[124]

Palivizumab is administered intramuscularly at a dosage of 15 mg/kg, packaged in 100 mg vials, and the opened vials should be used within 6 h.[125]

Palivizumab is administered once per month. The regime continues for a total of five doses, sufficient to provide protection during the entire RSV season which in Saudi Arabia usually extends from middle to late October and ends in early to mid-March.[121],[126]

This is different from the polyclonal RSV immune globulin intravenous (RSV-IGIV; RespiGamTM, MedImmune Inc., Gaithersburg, MD, USA) which is a hyper-immune polyclonal human intravenous antibody agent prepared from multiple donors. It used to be given as a monthly infusion at a dose of 750 mg/kg. Some disadvantages of prophylaxis with RSV-IGIV included the need for intravenous access; the fluid load (15 mL/kg) required to deliver the drug, the potential for transmission of blood-borne pathogens, and the interference with the antibody response to live-virus vaccines. Moreover, a significant increase in cyanotic episodes and cardiac surgery-related deaths was reported among children with cyanotic CHD and right to left shunt who were given RSV-IGIV,[134] thus limiting its use in children with CHD. RSV-IGIV is no longer marketed in the USA, and its use has been replaced by palivizumab.

Adherence to infection control practices is the basis for reducing healthcare-associated RSV disease. Till date, passive immune-prophylaxis against RSV infection with monoclonal antibodies is the only strategy that has demonstrated efficacy in reducing RSV hospitalizations in high-risk children. The lack of effective therapy against RSV infection makes prophylactic interventions the best strategy to avoid the acute and chronic complications of the disease.[127]

Palivizumab reduces RSV hospitalizations

Monthly administration of palivizumab throughout the RSV season was associated with reductions in RSV-related hospitalizations in all premature patient groups as revealed in the IMpact-RSV study.[100] It was observed that there was a significant reduction of 55% (95% CI: 38–72; P < 0.0001) in RSV-related hospitalizations in all infants and young children who received palivizumab versus those who received placebo (4.8% vs. 10.6%, respectively). A post hoc analysis of the original IMpact-RSV study was performed in 11 gestational age groups from the cohort of 724 premature infants and young children without CLD.[30] This analysis revealed that palivizumab significantly decreased the relative risk of RSV-related hospitalization (73%–82%, P < 0.05) compared with placebo in the 28wGA–31wGA, 29wGA–32wGA, 29wGA–33wGA, 32wGA–34wGA, and 32wGA–35wGA subgroups. Furthermore, the use of palivizumab consistently reduced RSV-related hospitalizations (64.5%–100%) compared with placebo in all 11 gestational age groups evaluated. Notably, relative reductions in risk for RSV-related hospitalizations were substantial for the moderate/late preterm infants and young children (82% for both the 32wGA–34wGA and 32wGA–35wGA groups).[30]

Results from the study by Feltes et al.[15] were consistent with those observed in the IMpact-RSV study. In young children with CHD, monthly prophylaxis with Palivizumab was associated with a significant reduction of 45% (95% CI: 23–67) in RSV-related hospitalizations following prophylaxis with Palivizumab compared with placebo (5.3% vs. 9.7%, respectively; P < 0.005).[15]

A systematic literature review and meta-analysis [128] conducted in 2014 combined the results from five randomized, placebo-controlled trials of palivizumab and assessed the safety and efficacy of palivizumab. The five studies included in the review were the IMpact-RSV trial,[121] the Feltes et al. study,[15] and three supplementary, nonpivotal trials, MAKI,[129] Subramanian [60] and Tasyo.[128] MAKI trial (2013) focused on the development of recurrent wheezing in preterm infants (33wGA to 35wGA) following the use of palivizumab for the prevention of RSV infection.[129] Subramanian (1998) was a Phase I/II multicenter, randomized, double-blind, placebo-controlled, dose-escalation trial of palivizumab on preterm infants (≤35wGA), and young children with BPD.[60] Tavsu (2014) assessed RSV-related hospitalization of preterm infants (<32wGA) following RSV prophylaxis with palivizumab.[130]

Although prophylaxis with palivizumab significantly reduces the incidence of RSV hospitalizations, some infants, and young children may still develop the breakthrough disease and require hospitalization. In the IMpact-RSV study, infants and young children randomized to palivizumab spent significantly fewer days in the hospital, required less supplemental oxygen and spent fewer days with a moderate or severe LRTI (P< 0.001 for all).[121]

Similar to the IMpact-RSV study, young children with HS-CHD receiving palivizumab prophylaxis had significantly fewer days of RSV hospitalization (P< 0.005) and increased oxygen requirement (P< 0.05).[15]

As such, it is speculated that prevention of RSV infection should reduce the rate of development of childhood recurrent wheezing and asthma. A double-blind, placebo-controlled trial from The Netherlands was performed to investigate the potential of Palivizumab in preventing the development of RSV-related wheezing during an infant's 1st year of life [129] RSV prophylaxis was shown to confer a relative reduction of 61% (95% CI: 56-65) in the total number of wheezing days during the 1st year of life (1.8% vs. 4.5%).[129]

During the 1-year follow-up period, the proportion of infants with recurrent wheeze was 10% lower in infants who received palivizumab compared with infants who did not (P< 0.05).

These data confirm that early RSV disease is an important mechanism in the pathogenesis of wheezing morbidity in this specific population and that prevention of early RSV disease may impact beneficially on the odds of developing wheezing during the 1st year of age.[129]

To determine whether immune-prophylaxis with palivizumab during infancy was associated with decreased childhood asthma, a retrospective cohort investigation was performed between 1996 and 2003.[137] Asthma was defined as 4.5–6 years of age and by using data from asthma-specific health-care visits and medication fills. Using multivariate logistic regression and propensity-score matched analysis, it was shown that infants who had 70% or greater adherence to palivizumab had decreased odds of developing asthma compared with infants with 20% or less adherence (OR: 0.62; 95% CI: 0.50–0.78).[137] RSV infections have been most frequently documented about asthma inception; it is possible that immune responses unique to this virus might also play a role in these outcomes.[138]

A prospective multicenter international cohort study of preterm infants was conducted to examine the relationship between RSV-related LRTIs in early life and rates of subsequent recurrent wheezing.[127] The study enrolled 191 preterm infants (≤35wGA) who had previously received palivizumab before 6 months of age and 230 who had never received palivizumab (76 who had been hospitalized due to RSV and 154 who had not). This study did not include infants with CLD or CHD. During the 2-year follow-up period, beginning at a mean age of 19 months, the incidence of reported recurrent wheezing was assessed according to the following definitions:[127]

An episode of wheezing: One or more consecutive days of wheezing, preceded and followed by a healthy period of at least 1 week

Recurrent wheezing: Three or more episodes of wheezing in a 12-month period, not necessarily documented by a physician

Physician-diagnosed recurrent wheezing: Three or more physician-diagnosed episodes of wheezing in a 12-month period.

A reduced incidence of recurrent wheezing was observed to be statistically significant in young children who previously received palivizumab compared with young children who have never received palivizumab (13% and 26%, respectively; P < 0.005)[127]

Safety

Safety data revealed that palivizumab at a dose of 15 mg/kg IM is safe and well tolerated.[139] In general, there were few differences in adverse event (AE) incidence among patients who had received palivizumab and those who had received placebo.[139]

The most common adverse effects were erythema at the injection site, fever, or diarrhea.[139] Discontinuation of palivizumab due to a drug-related AE is rare.

At a local level, a Phase II, single-arm, single-center, noncomparative, open-label, prospective study conducted in Saudi Arabia (Al-Alaiyan, 2015[125]), enrolled children at high risk for RSV infection and introduced up to seven monthly injections of palivizumab (15 mg/kg) during the 2000–2001 RSV season. Key enrollment criteria were no previous exposure to palivizumab and gestational age ≤35 weeks, ≤6 months of age at enrollment, or CLD and ≤24 months of age at enrollment. The aim of the study was to assess the safety, immunogenicity, and pharmacokinetics of palivizumab as an extended seven-dose regimen. Of 18 enrolled patients, 17 patients received seven palivizumab injections. The study concluded that an extended palivizumab regimen of up to seven monthly doses during the RSV season exhibited an acceptable safety profile in children at high risk for RSV infection in Saudi Arabia.[125]

Palivizumab reduces all-cause mortality rates

Prophylaxis with palivizumab has been shown to be associated with a reduction in all-cause mortality among preterm infants at high risk. A systematic review and meta-analysis of published literature between 1990 and 2007 was performed, including all RCTs, and prospective or retrospective cohort studies [140] Overall, it was observed that the all-cause mortality due to severe RSV disease was 0.19% in infants who received Palivizumab compared with 0.53% for infants without prophylaxis (OR: 0.30; 95% CI: 0.17-0.55).[140]

Cost benefit analysis

Several economic analyses of RSV immune-prophylaxis have been published and reviewed.[140],[141],[142] In general, cost-effectiveness studies are challenging to design and to compare since the items involved in the cost-effectiveness analysis vary considerably among Countries, social health-care systems, and pricing of the drug in different areas of the world.

For all the above-mentioned benefits of palivizumab the panel recommends the use of palivizumab for the immune-prophylaxis against RSV as per [Table 1] and documentation as per [Table 2].

Table 1: Recommendations on using Palivizumab across different patients categories.

RSV clinics shall dispense RSV prophylaxis from the beginning of October until the end of March

Palivizumab should be administered up to a maximum of 5 monthly doses (15 mg/kg/dose administered intramuscularly once every 28 days) during the RSV season to infants who qualify for prophylaxis. A child with a history of a severe allergic reaction following a dose of palivizumab should not receive additional doses

Qualified infants born during the RSV season must receive fewer doses according to their month of birth. For example, infants born in January would receive their last dose in March

Injection palivizumab should be stored in a refrigerator at 2°C–8°C

To reduce the risk for RSV and other viral infections, all infants, especially preterm infants, should be offered breast milk. The parents should be instructed to avoid smoke exposure, attendance at large group childcare during the first winter season and contact with ill people

It is recommended that household members should be immunized against influenza and practice good hand and cough hygiene

Palivizumab does not interfere with routine childhood immunizations.

Conclusion

In summary, bronchiolitis is the most common reason for hospital admission in the infancy period and is a major burden for any healthcare system.

According to the current evidence, management of bronchiolitis is mainly supportive and consists of oxygen administration, clearing the nasal airway secretions, and fluid balance maintenance.

Clinicians should pay special attention to the infants belonging to the high-risk groups for severe bronchiolitis.

There is growing evidence that hypertonic saline is an effective modality for treatment of inpatients as it is found to reduce the length of hospital stay. The available data does not support the routine use of bronchodilators, thus clinicians should limit their use to those cases with positive response only. There is modest benefit of using racemic epinephrine, and steroids whether inhaled or systemic are not effective. Some promising data exist for the use of Heliox and of noninvasive strategies of ventilation in severe cases, but more research is needed before a clear recommendation can be issued.

Currently, there is no available vaccine for RSV, the major causative pathogen of bronchiolitis, and immune-prophylaxis with palivizumab remains the mainstay of prevention in high-risk groups who qualify for this treatment. Cohorting, isolation, strict hygiene measures including accurate hand washing and use of personal equipment measures are crucial.

Acknowledgments

We would like to thank the two international experts Paolo Manzoni, MD, PhD and Xavier Carbonell-Estrany, MD, PhD for reviewing this manuscript.

Ochoa Sangrador C, González de Dios J, Research Group of the aBREVIADo Project. Overuse of bronchodilators and steroids in bronchiolitis of different severity: Bronchiolitis-study of variability, appropriateness, and adequacy. Allergol Immunopathol (Madr) 2014;42:307-15.

ABIM Foundation. American Board of Internal Medicine, ACP-ASIM Foundation. American College of Physicians-American Society of Internal Medicine, European Federation of Internal Medicine. Medical professionalism in the new millennium: A physician charter. Ann Intern Med 2002;136:243-6.

American Academy of Pediatrics Committee on Infectious Diseases and Committee on Fetus and Newborn. Revised indications for the use of palivizumab and respiratory syncytial virus immune globulin intravenous for the prevention of respiratory syncytial virus infections. Pediatrics 2003;112:1442-6.